In recent years much pharmacological research concerning .gamma.-aminobutyric acid (hereinafter designated GABA), an inhibitory neurotransmitter in the mammalian central nervous system, has been carried out.
The inhibition of GABA uptake results in enhanced availability of this inhibitory neurotransmitter in the synaptic cleft and thus to increased GABA'ergic activity. Increased GABA'ergic activity can be useful in the treatment, for example, of anxiety, pain and epilepsy as well as muscular and movement disorders (see, for example, P. Krogsgaard-Larsen et al., Progress in Medicinal Chemistry, 22 (1985) 68-112).
A well-known and potent inhibitor of GABA uptake from the synaptic cleft into presynaptic nerve terminals and glial cells is, for example, piperidine-3-carboxylic acid (nipecotic acid). However, being a relatively polar compound and therefore unable to cross the blood-brain barrier, piperidine-3-carboxylic acid itself has found no practical utility as a drug.
In U.S. Pat. No. 4,383,999 and No. 4,514,414 (SmithKline Beckman Corporation) and in EP 236342 as well as in EP 231996 (Novo Industri A/S) some derivatives of N-(4,4-disubstituted-3-butenyl)-azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, respectively (Novo Industri A/S) N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent are claimed as inhibitors of GABA uptake. EP 221572 (Warner-Lambert Company) claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.
According to Yunger, L. M. et al., J. Pharm. Exp. Therap. 228 (1984) 109, N-(4,4-diphenyl-3-buten-1-yl)nipecotic acid (designated SK&F 89976A), N-(4,4-diphenyl-3-buten-1-yl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-3-buten-1-yl)homo-.beta.-proline (designated SK&F 100561) and N-(4-phenyl-4-(2-thienyl)-3-buten-1-yl)nipecotic acid (designated SK&F 100604J) are orally active inhibitors of GABA uptake. These data are summarized in Krogsgaard-Larsen, P. et al., Epilepsy Res. 1 (1987) 77-93.
Guvacine is 1,2,5,6-tetrahydropyridine-3-carboxylic acid.